Osteoarthritis (OA) is an age-related degenerative joint disease that affects millions of people worldwide and is increasing in incidence as the population ages and becomes more obese. Significant loss of joint function, disability, and pain in the knees, hips, hands and spine are associated with OA, and its management places an enormous economic burden on healthcare systems. Current therapies manage OA symptoms, such as pain and inflammation, rather than addressing the cause of the disease: degradation of articular cartilage. We propose a novel, minimally invasive treatment that promotes self-repair of cartilage tissue, essentially reversing disease progression. Our Functional Cartilage Scaffold (FCS) consists of two principle components, an FDA-approved de-methylator, 5-azacytidine (5-Aza-CR), and cartilage-specific scaffold. When injected into an area of cartilage degradation, the methylation inhibitor is released from the scaffold and acts as an epigenetic modulator on local cells, prompting them to lose their identity and gain pluripotency and self-renewal capabilities. The reprogrammed cells then migrate to the cartilage matrix and trans- differentiate into functional cartilage-forming cells under the guidance of endogenous growth factors. In the final stage, reprogrammed cells remodel the extracellular matrix to form functional cartilage tissue. In this study, we will first characterize and optimize the composition and properties of our cartilage-specific scaffold and the retention and release of the epigenetic modulator. Second, we will assess the efficacy of the proposed strategy to make epigenetic modifications. Third, we will evaluate a FCS prototype in an animal model that closely resembles human OA development. These investigations will extend preliminary in vitro and in vivo studies, advance the system toward clinical application, and establish the treatment as a model for other diseases.